The NMD Pathway Regulates GABARAPL1 mRNA during the EMT

Abstract

EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during the EMT, many stress response pathways, such as autophagy and NMD, are dysregulated. Therefore, our goal was to study the regulation of ATG8 family members (GABARAP, GABARAPL1, LC3B) by the NMD and to identify molecular links between these two cellular processes that are involved in tumor development and metastasis formation. IHC experiments, which were conducted in a cohort of patients presenting lung adenocarcinomas, showed high GABARAPL1 and low UPF1 levels in EMT+ tumors. We observed increased levels of GABARAPL1 correlated with decreased levels of NMD factors in A549 cells in vitro. We then confirmed that GABARAPL1 mRNA was indeed targeted by the NMD in a 3′UTR-dependent manner and we identified four overlapping binding sites for UPF1 and eIF4A3 that are potentially involved in the recognition of this transcript by the NMD pathway. Our study suggests that 3′UTR-dependent NMD might be an important mechanism that is involved in the induction of autophagy and could represent a promising target in the development of new anti-cancer therapies.

SMG1:SMG8:SMG9-complex integrity maintains robustness of nonsense-mediated mRNA decay

“…Gene ontology analysis did not reveal any significant pathways associated with the observed differential expression patterns (Figure 1E). Of note, previously identified NMD-sensitive marker mRNAs, such as GADD45B, ZFAS1 or GABARAPL1 33–35 remained unchanged, indicating that NMD activity is not globally altered. To test the NMD-status of the delKID cells in more detail, we turned to transcript isoform-specific analyses.…”